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Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab
Abstract
Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)—ipilimumab and tremelimumab—have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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“We observed an association between irAEs and improved PFS using a landmark analysis, in agreement with previous studies58–60, and uncovered that baseline gut microbiome composition segregated PD-1-treated patients who developed irAEs from those who did not.”
From Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 (2022) · cites this paper as [60]
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“from immunotherapy, such as severe rashes and colitis [23,24].”
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“Al ‐ though a large proportion of irAEs can be relieved by steroid administration (Weber et al., 2012), identify ‐ ing predictive biomarkers, such as TME genes, tumor mutation burden (TMB), gastrointestinal irAEs, and CD39 + tumor-resident cytotoxic T cells, is crucial for determining the potential…”
Long-Term Toxicities of Immune Checkpoint Inhibitors
Abraham, P. E., & Johnson, D. B. (2025) · Drugs · doi:10.1007/s40265-025-02243-4 · Cited by 23
“There is a higher incidence of cutaneous irAEs with patients on anti-CTLA-4 therapies (both monotherapy or combination) as opposed to anti-PD-1/P-L1 monotherapies [123, 127, 128].”
Prevention and management of cutaneous immune‐related adverse events: EADV Task Force statement
Fattore, D., Apalla, Z., Freites‐Martínez, A., Tommasino, N., Nikolaou, V. A., Lauletta, G., Ortiz‐Brugués, A., Sollena, P., Starace, M. V. R., Gomes, N. P., et al. (2025) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.70149 · Cited by 18
“41 Dermatologic assessment is advised in severe or atypical cases or if refractory to initial treatment.”
Ngamphaiboon, N., Ithimakin, S., Siripoon, T., Sintawichai, N., & Sriuranpong, V. (2021) · BMC Cancer · doi:10.1186/s12885-021-09003-z · Cited by 18
“On the other hand, patients treated with ipilimumab had skin, and GI-related AEs after 2–3 weeks, and 6 to 7 weeks, respectively [22].”
BackgroundAlghamdi, E. A. S., Aljohani, H. I., Alghamdi, W., & Alharbi, F. (2022) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2022.06.010 · Cited by 18
“( Weber et al., 2012).”
Özdemir, B. C., da Silva, C. E., Arangalage, D., Monney, P. A., Guler, S. A., Huynh‐Do, U., Stirnimann, G., Possamai, L. A., Trepp, R., Hoepner, R., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03436-0 · Cited by 18
“Hepatitis is usually observed after 7–8 weeks of treatment, but an earlier manifestation is possible [25, 26].”
BackgroundGibney, G. T., & Atkins, M. B. (2015) · PubMed · Cited by 18
2015 Guidance on cancer immunotherapy development in early‐phase clinical studies
Working Group for Effector Cell Therapy, Working Group for Cancer Vaccines and Adjuvants, & Working Group for Anti‐immune Checkpoint Therapy and Comprehensive Cancer Immunotherapy (2015) · Cancer Science · doi:10.1111/cas.12819 · Cited by 17
Menis, J., Litière, S., Tryfonidis, K., & Golfinopoulos, V. (2016) · Annals of Translational Medicine · doi:10.21037/atm.2016.06.19 · Cited by 20
“An additional challenge in establishing the RP2D has also been the observation that, contrary to the classical model, an increase in the dose of the current classes of imAbs does not necessarily result in an increased rate of activity or toxicity (5,6,10-12).”
BackgroundResultCutaneous Manifestations of Reactions to Biologics
Otani, I. M., Levin, A. S., & Banerji, A. (2018) · Current Allergy and Asthma Reports · doi:10.1007/s11882-018-0764-z · Cited by 19
Gazzé, G. (2018) · Melanoma Management · doi:10.2217/mmt-2017-0026 · Cited by 18
Herlihy, J. D., Beasley, S., Simmelink, A., Maddukuri, V. C., Amin, A., Kamionek, M., Jacobs, C., Bossi, K. L., & Scobey, M. (2019) · Southern Medical Journal · doi:10.14423/smj.0000000000000944 · Cited by 18
Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review
Dudzińska, M., Szczyrek, M., Wojas‐Krawczyk, K., Świrska, J., Chmielewska, I., & Zwolak, A. (2020) · Cancers · doi:10.3390/cancers12082314 · Cited by 19
“The effect of anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies on immune processes is associated with the possibility of adverse effects (AE) related to the activity of the immune system, the infiltration of normal tissue by activated T lymphocytes and organ-specific autoimmune reactions which include, among others, pn…”
BackgroundMantia, C. M., & Buchbinder, E. I. (2019) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2018.12.008 · Cited by 18
Novel Treatments for Melanoma Brain Metastases
Kenchappa, R. S., Tran, N., Rao, N. G., Smalley, K. S. M., Gibney, G. T., Sondak, V. K., & Forsyth, P. A. (2013) · Cancer Control · doi:10.1177/107327481302000407 · Cited by 18
Management of pulmonary toxicity associated with targeted anticancer therapies
Teuwen, L.-A. M. N., den Mooter, T. V., & Dirix, L. Y. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.1080687 · Cited by 18
“First of all, an early diagnosis and initiation of treatment is critical to accomplish a successful resolution of these toxicities and reduce the risk of severe complications [82,83].”
BackgroundKıratlı, H., Mocan, M. C., & Irkec, M. T. (2016) · Case Reports in Ophthalmology · doi:10.1159/000448730 · Cited by 18
Understanding Immune Checkpoint Inhibitors for Effective Patient Care
Rubin, K. M. (2015) · Clinical journal of oncology nursing · doi:10.1188/15.cjon.709-717 · Cited by 23
“For this reason, thyroid and liver enzyme levels should be monitored prior to commencing treatment (Bristol-Myers Squibb, 2015a, 2015b; Fecher et al., 2013; Weber et al., 2012), with ongoing periodic monitoring during and after treatment (Bristol-Myers Squibb, 2015a, 2015b; Merck & Co., 2015).”
Sanchez, K. G., Page, D. B., & Urba, W. J. (2019) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2019.02.009 · Cited by 18
Cardiotoxicity of Biological Therapies in Cancer Patients: An In-depth Review
Madanat, L., Gupta, R., Weber, P., Kumar, N., Chandra, R., Ahaneku, H. P., Bansal, Y., Anderson, J., Bilolikar, A., & Jaiyesimi, I. A. (2022) · Current Cardiology Reviews · doi:10.2174/1573403x18666220531094800 · Cited by 20
“However, their increased use in the setting of malignancy has led to a corresponding increase in side effects, better known as immune-related adverse events (IRAEs) [22-24].”
BackgroundManaging Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors
Cheema, P. K., Iafolla, M. A. J., Abdel-Qadir, H. M., Bellini, A. B., Chatur, N., Chandok, N., Comondore, V. R., Cunningham, M. E., Halperin, I. J., Hu, A. C., et al. (2024) · Current Oncology · doi:10.3390/curroncol31100473 · Cited by 18
Update on New Therapies With Immune Checkpoint Inhibitors
Peterson, J., & Steele-Moses, S. K. (2016) · Clinical journal of oncology nursing · doi:10.1188/16.cjon.405-410 · Cited by 17
The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis
Puri, A., & Homsi, J. (2017) · Melanoma Research · doi:10.1097/cmr.0000000000000387 · Cited by 17
Mishima, Y., Fukaishi, T., Inase, N., & Isogai, S. (2018) · Internal Medicine · doi:10.2169/internalmedicine.1268-18 · Cited by 17
“It was reported that patients with ipilimumab-induced hypothyroidism could continue ipilimumab treatment with thyroid hormone replacement (17).”
BackgroundCheckpoint inhibitors: What gastroenterologists need to know
Ahmed∥, M. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i48.5433 · Cited by 17
Kähkönen, T. E., Halleen, J. M., & Bernoulli, J. (2020) · Cancers · doi:10.3390/cancers12061615 · Cited by 16
“The anti-CTLA-4 antibody ipilimumab that has been approved for the treatment of metastatic melanoma and advanced renal cell carcinoma is associated with severe irAEs, including rash and colitis [115].”
BackgroundAbu-Shawer, O., Singh, P., Yenulevich, E., Brito, A., Ni, J., Abdulnour, R.-E. E., Grover, S., Manos, M. P., Bowling, P. J., LeBoeuf, N. R., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000992 · Cited by 16
George, A. S., Fernandez, C. J., Eapen, D., & Pappachan, J. M. (2021) · touchREVIEWS in Endocrinology · doi:10.17925/ee.2021.17.1.21 · Cited by 18
Metadata
- Authors
- Weber, J. S., Kähler, K. C., & Hauschild, A.
- Affiliations
- Moffitt Cancer Center (US)
- Venue
- Journal of Clinical Oncology
- Published
- 2012-07-20
- Volume
- 30
- Issue
- 21
- Pages
- 2691-2697
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2109653150
- Cited by
- 1,415
- References
- 33
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 59 · 2023: 79 · 2022: 84 · 2021: 117 · 2020: 129 · 2019: 123 · 2018: 146 · 2017: 153 · 2016: 152 · 2015: 145 · 2014: 94 · 2013: 65 · 2012: 9
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- ipilimumab, immune-related adverse events, CTLA-4 blockade, metastatic melanoma, immune checkpoint inhibitors, toxic epidermal necrolysis, colitis, hypophysitis, hepatitis, iridocyclitis, neuropathy, nephritis, adverse event management
- MeSH terms
- Ipilimumab, Antibodies, Monoclonal, Antineoplastic Agents, Colitis, Drug Eruptions, Diarrhea, Humans, Liver, Lymphatic Diseases, Melanoma, Mucous Membrane, Pancreatitis, Peripheral Nervous System Diseases, Pituitary Gland, Skin, Skin Neoplasms, Stevens-Johnson Syndrome, Uveitis, Scleritis, Chemical and Drug Induced Liver Injury, CTLA-4 Antigen, Antibodies, Monoclonal, Humanized
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